Massage therapy [in the form of Manual Lymph Drainage (MLD)] is an integral component, with compression bandaging (CB), of Combined Physical Therapy (CPT), the international consensus-recommended optimal treatment for peripheral lymphedema (LE). According to the World Health Organization, LE afflicts hundreds of millions worldwide (most from parasitic filarial infestation) and probably millions in the United States (most from operative and irradiation treatment of cancer). For more than a century, close links between various forms of massage and salutary effects on lymph circulation have been postulated but the efficacy of MLD alone without CB remains to be convincingly demonstrated. New experimental data derived from our NCCAMR21 funded investigation of a rat subacute LE model mimicking cancer-treatment related unilateral LE (radical groin lymphectomy/lymphadenectomy + irradiation) suggests that MLD alone reduces established LE volume as effectively as CB and CPT while minimizing LE development. As an initial translation of these experimental findings to patients and based on our retrospective clinical observations, we propose to examine prospectively the short-term and long-term efficacy of MLD alone compared to MLD + CB as part of CPT in a randomized trial in patients with mild (5-20% increase in arm volume) breast cancer treatment-related LE using and further developing both objective (serial arm LE volume reduction and lymphatic tracer transport enhancement using minimally invasive lymphangioscintigraphy) and standardized subjective/qualitative outcome measures (improved quality of life/compliance/cost-benefit scores). This initial study should lay the groundwork and evidence-based rationale for the design and implementation of expanded prospective randomized clinical trials of MLD alone in various types and stages of upper and lower extremity LE in children and adults. This combined experimental and clinical translational approach should thereby shed light not only on the physiologic mechanisms underlying massage therapy but also have potentially substantial impact on simpler cost-effective LE treatment alternatives worldwide.